Effects of Short-Term and Long-Term Pretreatment of Schisandra Lignans on Regulating Hepatic and Intestinal CYP3A in Rats

Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Drug metabolism and disposition: the biological fate of chemicals (Impact Factor: 3.25). 10/2009; 37(12):2399-407. DOI: 10.1124/dmd.109.027433
Source: PubMed


This study aimed to evaluate the effects of Schisandra lignan extract (SLE) with short- and long-term pretreatment on regulating rat hepatic and intestinal CYP3A for a comprehensive evaluation of metabolism-based herb-drug interactions. Inhibitory effects of SLE and its major components on rat CYP3A were confirmed in both hepatic and intestinal microsomal incubation systems. After a single dose of SLE pretreatment, higher C(max) and area under the concentration-time curves from zero to infinity (AUC(0-infinity)) values were observed for intragastric midazolam (MDZ), whereas those for the intravenous MDZ were little changed. The mechanism-based inhibition of SLE toward CYP3A was further confirmed in vivo, characterized with a recovery half-life of 38 h. In contrast, SLE long-term treatment enhanced both hepatic (2.5-fold) and intestinal (4.0-fold) CYP3A protein expression and promoted the in vivo clearance of MDZ. When MDZ was coadministered with SLE after a consecutive long-term treatment, the AUC(0-infinity) value of MDZ was still lower than that of the control group, suggesting a much stronger inducing than inhibiting effect of SLE toward CYP3A. Furthermore, the intragastric administration of SLE exhibited a more intensive regulating effect toward intestinal than hepatic CYP3A, which could be partially explained by the relatively high exposures of lignans in the intestine. In conclusion, this study provides a comprehensive map for showing the complicated effects of SLE and its components on regulating rat CYP3A. The important findings are that SLE possesses a much stronger inducing than inhibiting effect on CYP3A, as well as a more intensive regulating effect on intestinal than hepatic CYP3A.

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    • "Previous reports (Mu et al., 2006) demonstrated that Schisandra lignan extract also induced both CYP3A and CYP2C expression through activating orphan nuclear receptor pregnane X receptor, probably by exerting a biphasic effect (short-term inhibition and long-term induction) on regulating CYP3A expression and activity, which was also observed with St. John's Wort (Rengelshausen et al., 2005; Xie and Kim, 2005). More recently, it was found that long-term administration of the Schisandra lignan extract induced both intestinal and hepatic CYP3A protein expression (Lai et al., 2009), suggesting that WZC exhibited a mechanism-based induction toward CYP3A. In combinatorial considerations, we were interested in investigating the net effect of coadministration with WZC on exposure tacrolimus. "
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    ABSTRACT: Wuzhi capsule (WZC) is a preparation of an ethanol herbal extract of Schisandra sphenanthera(Nan-Wuweizi), with its main active ingredients including schisandrin, schisandrol B, schisantherin A, schisanhenol and deoxyshisandrin. WZC and tacrolimus are often co-administered for the treatment of drug-induced hepatitis in organ transplant recipients in China. Recently, it was reported that WZC could significantly increase the blood concentration of tacrolimus. The purpose of this study was to investigate whether and how WZC affects the pharmacokinetics of tacrolimus in rats. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine the plasma concentration of tacrolimus. The results showed that WZC increased the mean plasma concentration of tacrolimus. Compared with administration of tacrolimus alone (Cmax, 18.87±10.29 ng/mL; AUC0&→t, 40.98±37.07), a single intragastric administered dose of WZC increased, the pharmacokinetic parameters of tacrolimus (Cmax, 59.42±30.32 ng/mL; AUC0→t, 239.71±28.86) by five folds in rat plasma. After pretreatment with WZC for 12 days, there were still significant increases in AUC0→t (from 40.98±37.07 to 89.21±26.39 h ng/mL; p < 0.05) and Cmax (from 18.87±10.29 to 43.16±10.61 ng/mL; p < 0.05) of tacrolimus compared with oral of tacrolimus alone, suggesting that WZC increased the exposure of tacrolimus by one or more mechanisms. The increase in tacolimus Cmax by WZC was dose dependent. The effect of WZC on Tacrolimus AUC0→t also increased with dose with a maximal effect observed at 450 mg/kg (825.34 ng h/mL). No further increases in tacolimus AUC0→t were observed at WZC dose above 450 mg/kg. It is suggested that due to the effect of WZC on the pharmacokinetics of tacrolimus, the herb-drug interaction between WZC and tacrolimus should be taken into considered in clinical practice.
    Drug metabolism and disposition: the biological fate of chemicals 04/2013; 41(7). DOI:10.1124/dmd.112.050302 · 3.25 Impact Factor
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    • "The data show that SchE also could markedly increase the blood concentration and oral bioavailability of midazolam in healthy men (Xin et al. 2009). Then the inhibitory influence of SchE on CYP3A is supported by subsequent reports (Qin et al. 2010; Lai et al. 2009; Mu et al. 2006). And it has been proved that methanol fraction of Schisandra fruit has a strong inhibitory effect on human liver microsomal CYP3A4 in vitro with IC 50 value of 127 ␮g/ml, which was similar to the value (105 ␮g/ml) for inhibition of erythromycin N-demethylation activity in human intestinal microsomes. "
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    ABSTRACT: To investigate the possible drug interaction, this study is designed to evaluate the ability of Schisandrin B (Sch B) to modulate cytochrome P450 3A activity (CYP3A) in vivo and to alter the pharmacokinetic profiles of CYP3A substrate (midazolam) in treated rats. Rats were repeated administered with physiological saline (negative control group), ketoconazole (75mg/kg, positive control group) or varied doses of Sch B (experimental groups) for three consecutive days. Subsequently, changes in hepatic microsomal CYP3A activity and the pharmacokinetic profiles of midazolam and 1'-hydroxy midazolam in plasma were studied to evaluate CYP3A activity. The results indicated that Sch B significantly dose-dependently inhibited rat hepatic microsomal CYP3A activity with Ki value of 16.64mg/kg and showed the characteristic of a noncompetitive inhibitor. Oral administration of Sch B for 3 days in rats produced significant effect on the pharmacokinetics of oral midazolam. Sch B resulted in a significant, dose-dependent increase in midazolam AUC0-∞ except at the dose of 2mg/kg, while AUC0-∞ increased by 26.1% (8mg/kg) and 60.6% (16mg/kg), respectively. In the pharmacokinetic profiles of 1'-hydroxy midazolam, the significant, dose-dependent decrease in AUC0-∞ was observed except at the dose of 2mg/kg, while AUC0-∞ reduced by 44.5% (8mg/kg) and 49.2% (16mg/kg), respectively. These results suggested that 3-day treatment of Sch B could increase concentration and oral bioavailability of drug metabolized by CYP3A. When the drug, consisting of Sch B, is used in the clinic for more than 3 days, the possible drug-drug interactions should be taken into consideration.
    Phytomedicine: international journal of phytotherapy and phytopharmacology 03/2013; 20(8-9). DOI:10.1016/j.phymed.2013.02.005 · 3.13 Impact Factor
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    • "报道一致, 但文献报道在 14 天看 到 CYP3A 酶活性的诱导, 而本研究在整体给药后第 6 天就发现五味子水提物对 CYP3A 酶活性的显著诱 导作用; 且文献 [12] 中还提到给予五味子提取物 3 天 后, CYP3A 酶活性的抑制作用逐渐恢复到正常水平, 和本实验在第 3 天观察到的现象完全一致。本研究 结合文献 [12] 证实, 五味子提取物对大鼠 CYP3A 酶活 性在时间上呈现先抑制后诱导的双重作用。 在大鼠肝微粒体孵育体系中, 按照五味子水提 物的得率换算, 五味子水提物的 IC 50 相当于 1.95 g·L −1 生药浓度; 且在整体给药 12 h 后, 五味子 1 g·kg −1 剂量组可以降低 CYP3A 酶活性到 50%左右, 按照体 外 IC 50 值推算给药剂量, 即使只有 50%的药物吸收, 此剂量组也可产生抑制酶活性作用, 说明整体与离 体实验结果高度相关。 在离体大鼠肝微粒体中, 除了 Iwata [8] 发现的 5 种 木脂素组分外, 本实验还发现南五味子素具有强抑制 CYP3A 酶活性的作用, 且 IC 50 < 10 μmol·L −1 ; 同时未 见五味子甲素有显著抑制作用 (IC 50 > 100 μmol·L −1 )。 · 1198 · 药学学报 Acta Pharmaceutica Sinica 2010, 45 (9): 1194−1198 CYP3A1 亚型是大鼠肝脏 CYP3A 亚族中的主要 同工酶, 在药物代谢过程中起重要作用 [17] "
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    ABSTRACT: This study is to investigate the effects of aqueous extract of Schisandra chinensis Baill (WWZ), kadsurin, schisandrin A, schisandrin B and schisandrol B on rat hepatic CYP3A. Rats received a daily gavage of aqueous extract of WWZ for different times. The livers were harvested after gavage and subjected to microsome preparation. Microsomal CYP3A activity was determined by measuring the amount of the metabolite of testosterone (6 beta-hydroxytestosterone) with HPLC. Aqueous extract of WWZ, kadsurin and schisandrin A were incubated with microsomes obtained from rat. Microsomal CYP3A activity was determined by HPLC. Primary hepatocytes were separated and extracted from rat, then were treated with aqueous extract of WWZ, schisandrin A, schisandrin B and schisandrol B. Then, the expression of CYP3A1 mRNA was analyzed by RT-PCR. As for the in vivo assay, aqueous extract of WWZ significantly inhibited the enzyme activity of CYP3A after 12 h gavage. The inhibitory effect was converted to inductive effect after 3-day gavage. Aqueous extract of WWZ could induce the enzyme activity of CYP3A after 6-day gavage. Aqueous extract of WWZ and kadsurin showed a dose-dependent inhibition of CYP3A (IC50 of 487.8 microg mL(-1) and 6.2 micromol L(-1), separately). In rat primary hepatocytes, aqueous extract of WWZ (2.5 mg mL(-1)), schisandrin A (0.1 micromol L(-1)), schisandrin B (0.1 micromol L(-1)) and schisandrol B (10 micromol L(-1)) increased significantly the expression of CYP3A1 mRNA by 23%, 55%, 42% and 27%, respectively. Aqueous extract of WWZ could show dual effect on the enzyme activity of CYP3A in rat in vivo. Meanwhile, kadsurin showed a dose-dependent inhibition of the enzyme activity of hepatic CYP3A in vitro. And schisandrin A, schisandrin B and schisandrol B showed significant inductive effect on the expression of rat CYP3A1 mRNA.
    Yao xue xue bao = Acta pharmaceutica Sinica 09/2010; 45(9):1194-8.
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